A long standing goal of this Section has been the development of new therapeutic and preventative strategies for human herpesvirus infections and better definition of their pathogenesis. Notable past achievements have included the development of acyclovir as a suppressive treatment for recurrent oral and genial herpes and identification of drug resistant strains in immunocompetent patients.We recently reported the results of a study aimed at determining why some people develop frequently symptomatic herpes outbreaks while others do not. We compared HLA haplotypes in 3 sets of subjects: individuals who are seronegative for both HSV1 and 2, individuals who are seropositive for HSV2 but fail to recognize recurrent outbreaks, and individuals who are HSV2-positive and have frequent clinical outbreaks. We have identified statistically significant haplotypes that distinguish patients with frequent recurrences from uninfected individuals and individuals with no symptoms and which distinguish infected form uninfected persons.A second major goal of this section is the elucidation of pivotal molecular and cellular events which define and contribute to the pathogenesis of acute , chronic, and recurring infections with human herpesviruses. Major current projects fall into two areas: (1) Analysis of infection and gene expression by varicella- zoster virus; and (2) Comparative biology and molecular analysis of latent infections of animals and humans with herpes simplex virus types-1 and 2.As regards to studies of VZV infection we have identified specific genes that are expressed during virus latency in human cells. In this regard, we are currently examining the regulation, transcription, expression, and persistence of VZV gene 21, whose product appears to be expressed during latency in infected rats and humans. We reported detailed mapping of the VZV gene 21 transcript and the responsiveness of its promoter to VZV transregulatory genes. In 2 separate studies we examined latent VZV and HSV gene load and expression. We developed and reported a novel model of latent VZV infection by intraperitoreal injection of neonatal rats. Preliminary data using PCR show latent genome in most animal trigeminal ganglia at 4-6 weeks post-infection, and presence of gene 21 but not gene 40 message, in accord with data from human studies. In a second study, we developed and standardized a series of quantitative fluorescence PCR assays by which we can measure the number of copies of latent HSV and VZV genes in human tissues harvested at autopsy. In the first such study, we identified a mean of 258 copies of the VZV genome per 100,000 human trigeminal ganglion cells. The quantity of latent HSV-1 in these ganglia was about 10 fold higher.In other studies, we cloned and expressed VZV envelope glycoproteins in baculovirus. We are studying the interactions among these proteins and with cell surface molecules.As regards studies of HSV latency, we have refined mouse ocular models of HSV-1 and 2 infection. We can establish latency, quantitate virus load, latency gene expression, and induce reactivations with heat of ultraviolet heat. We used this model to study the relative potency of new antiviral drugs in preventing latency, and the role of several cytokines in establishment of latency and reactivates by infecting gene knockout mice.In our most important new initiative, we have generated mice transgenic for 5.5kb of the HSV- 2 genome containing the promoter and coding region for the major latency associated transcripts (LATs). Thus far, we have prepared 5 founders, bred one of them to homogeneity and proved expression of LATs in numerous tissues including sensory neurons. - Acyclovir, herpes simplex virus, genital herpes, viral pathogenesis, virus latency - Human Subjects